Klinefelter Syndrome in Adolescence: Onset of Puberty Is Associated with Accelerated Germ Cell Depletion

Abstract

The process of germ cell depletion in patients with Klinefelter syndrome (KS) is incompletely characterized. In the current work, we evaluated the presence of germ cells in adolescent boys with KS for possible future use in assisted reproduction techniques. Fourteen nonmosaic 47,XXY boys (aged 10-14 yr) were enrolled. Every fourth month their puberty was staged, and serum was obtained for hormone analyses. Each boy underwent a single testicular biopsy. Biopsy specimens of seven peripubertal boys (testicular volume < 2.0 ml) had spermatogonia of adult type, whereas older boys with larger testes (> 2.0 ml) exhibited no germ cells. No meiotic germ cells were detectable in any of these subjects. Depletion of germ cells was associated with an increase in testicular volume but was not immediately reflected in levels of serum gonadotropin, inhibin B, or anti-Müllerian hormone. In contrast, hypergonadotropism and suppression of serum inhibin B and anti-Müllerian hormone developed later, during midpuberty, after an unequivocal increase in serum testosterone (>2.5 nmol/liter) levels and degeneration of Sertoli cells. In conclusion, these prepubertal and early pubertal boys with KS had diploid germ cells that vanished in early puberty when testicular volume increased, whereas serum gonadotropin and inhibin B levels displayed pathological changes later during midpuberty.

Germ cell loss is associated with fading Lin28a expression in a mouse model for Klinefelter's syndrome

“…This finding is in contrast to other studies that report normal testicular histology and germ cell numbers during the foetal period of KS patients (Gustavson & Kjessler 1978, Flannery et al 1984. Other studies analysing testis material from the neonatal and prepubertal period have found reduced numbers of germ cells (Ferguson-Smith 1959, Mikamo et al 1968, Edlow et al 1969, Muller et al 1995, Wikstrom et al 2004. With such disparate data, it is difficult to derive any meaningful conclusions, a situation further complicated by the fact that the KS boys were partially cryptorchid, a factor known to cause a marked decrease in germ cell number independent of karyotype (Hadziselimovic & Herzog 2001).…”

“…With such disparate data, it is difficult to derive any meaningful conclusions, a situation further complicated by the fact that the KS boys were partially cryptorchid, a factor known to cause a marked decrease in germ cell number independent of karyotype (Hadziselimovic & Herzog 2001). Wikstrom et al (2004) showed that the depletion of germ cells accelerated with increasing testosterone levels at the onset of puberty, culminating in the complete loss of germ cells. A finding that led to the proposition that meiotic failure occurring during this phase (i.e.…”

Therapy of endocrine disease: Testicular function and fertility in men with Klinefelter syndrome: a review

“…Accordingly, Wikstrom et al (17) only found germ cells in the testes of 50% of peripubertal Klinefelter boys indicating that the fertility may already be impaired at this young age. In addition, Wikstrom et al (18) showed that germ cell differentiation was arrested in spermatogonium or early spermatocyte stage in KS, and that the spermatogonia undergo apoptosis instead of entering meiosis at the onset of puberty.…”

Sperm retrieval from patients with nonmosaic Klinefelter’s syndrome by semen cytology examination

“…Increased male age is strongly associated with a decline in male spermatogenesis. Some studies have described that age is a limiting factor for successful sperm retrieval in nonmosaic KS males and suggested that earlier infertility assessment and testicular sperm extraction in men with KS might play a critical role in their treatment (Wikstrom et al, 2004;Emre et al, 2006). Wikstrom et al (2004) found that only 50% of the boys with KS had germ cells in their testes, indicating a severely impaired fertility potential even in the peripubertal period.…”

“…Some studies have described that age is a limiting factor for successful sperm retrieval in nonmosaic KS males and suggested that earlier infertility assessment and testicular sperm extraction in men with KS might play a critical role in their treatment (Wikstrom et al, 2004;Emre et al, 2006). Wikstrom et al (2004) found that only 50% of the boys with KS had germ cells in their testes, indicating a severely impaired fertility potential even in the peripubertal period. Therefore, a potential strategy for infertility in patients with KS is cryopreservation of ejaculated spermatozoa or testicular tissue early in the patients' adolescence (Sousa et al, 2002;Ichioka et al, 2006).…”